3-heteroaryl-2-indolinone compounds for the treatment of disease

• US 5,792,783 A
• Filed: 06/05/1996
• Issued: 08/11/1998
• Est. Priority Date: 06/07/1995
• Status: Expired due to Term

• Current Assignee: Sugen Incorporated (Pharmacia Corp.)
• Original Assignee: Sugen Incorporated (Pharmacia Corp.)
• Inventors: Tang, Peng Cho, Sun, Li, McMahon, Gerald
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US08/655,223
• Time in Patent Office: 797 Days
• Field of Search: 548/468, 548/125, 548/127, 548/128, 548/131, 548/134, 548/136, 548/143, 548/202, 548/214, 548/235, 548/247, 548/250, 548/255, 548/266.4, 548/312.1, 548/364.7, 514/414, 514/359, 514/361, 514/362, 514/363, 514/364, 514/365, 514/372, 514/374, 514/378, 514/381, 514/383, 514/397, 514/406
• US Class Current: 514/397
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/02 of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
• CPC Class Codes: A61P 5/06 of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
• CPC Class Codes: A61P 5/08 for decreasing, blocking or antagonising the activity of the anterior pituitary hormones
• CPC Class Codes: A61P 5/10 of the posterior pituitary hormones, e.g. oxytocin, ADH
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 209/34 : in position 2
• CPC Class Codes: C07D 403/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/06 : linked by a carbon chain containing only aliphatic carbon atoms

Abstract

The present invention relates to organic molecules capable of modulating tyrosine kinase signal transduction in order to regulate, modulate and/or inhibit abnormal cell proliferation.

Claims

1. A compound having the formula:

##STR11## or a pharmaceutically acceptable salt thereof, wherein;

R₁ is H;

R₂ is O or S;

R₃ is hydrogen;

R₄, R₅, R₆, and R₇ are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO₂ NRR'"'"', SO₃ R, SR, NO₂, NRR'"'"', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH₂)_n CO₂ R, and CONRR'"'"';

A is a five membered heteroaryl ring selected from the group consisting of thiophene, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole, isothiazole, 2-sulfonylfuran, 4-alkylfuran, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3,4-thiatriazole, 1,2,3,5-thiatriazole, and tetrazole, optionally substituted at one or more positions with alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO₂ NRR'"'"', SO₃ R, SR, NO₂, NRR'"'"', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH₂)_n CO₂ R or CONRR'"'"';

n is 0-3;

R is H, alkyl or aryl; and

R'"'"' is H, alkyl or aryl;

wherein said compound regulates, inhibits or modulates tyrosine kinase signal transduction;

with the proviso that the following compounds are excluded;

3- (pyrrol-2-yl)methylene!-2-indolinone;

3- (5-chloro-3,4-dimethylpyrrol-2-yl)methylene!-2-indolinone;

3- (3,5-dimethyl-4-ethylpyrrol-2-yl)methylene!-2-indolinone;

3- (3,5-dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene!-2-indolinone;

Benzoic acid, 2- 1-ethyl-2,3-dihydro-2-oxo-3-(1H-pyrrol-2-ylmethylene-1H-indol-5-yl!)oxy!methyl!-;

3- (1-methyl-5-nitro-imidazol-2-yl)methylene!-2-indolinone;

3-(thien-2ylmethylene)-2-indolinone;

1H-Indole-7-acetic acid, 3- (2-butyl-1H-imidazol-4-yl)methylene!-2,3-dihydro-2-oxo-, ethyl ester; and

1H-Indole-7-acetic acid, 3- (2-butyl-1- (1,1-dimethylethoxy)carbonyl!-1H-imidazoI-4-yl)methylene!-2,3-dihydro-2-oxo-, ethyl ester.

5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound according to claim 1.

2. A compound having the formula:

##STR12## or a pharmaceutically acceptable salt thereof, wherein;

R₁ is H;

R₂ is O or S;

R₃ is hydrogen;

R₄, R₅, R₆, and R₇ are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO₂ NRR'"'"', SO₃ R, SR, NO₂, NRR'"'"', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH₂)_n CO₂ R, and CONRR'"'"',

A is a five membered heteroaryl ring selected from the group consisting of pyrazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole, isothiazole, 2-sulfonylfuran, 4-alkylfuran, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3,4-thiatriazole, 1,2,3,5-thiatriazole, and tetrazole, optionally substituted at one or more positions with alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO₂ NRR'"'"', SO₃ R, SR, NO₂, NRR'"'"', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH₂)_n CO₂ R or CONRR'"'"';

n is 0-3;

R is H, alkyl or aryl; and

R'"'"' is H, alkyl or aryl.

6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound according to claim 2.

7. The pharmaceutical composition of claim 6, wherein said composition is suitable for parenteral administration to a subject.

8. The pharmaceutical composition of claim 7, wherein said composition is suitable for subcutaneous administration to a subject.

9. The pharmaceutical composition of claim 6, wherein said composition is in a depot formulation.

3. A compound selected from the group consisting of 3- (3-Methylpyrrol-2-yl)methylene!-2-indolinone;

3- (3,4-Dimethylpyrrol-2-yl)methylene!-2-indolinone;

3- (2-Methylthien-5-yl)methylene!-2-indolinone;

3- (3-Methylthien-2-yl)methylene!-2-indolinone;

3-{ 4-(2-methoxycarbonylethyl)-3-methylpyrrol-5-yl)!methylene}-2-indolinone;

3- (4,5-Dimethyl-3-ethylpyrrol-2-yl)methylene!-2-indolinone;

3- (5-Methylimidazol-2-yl)methylene!-2-indolinone;

5-Chloro-3- (5-methylthien-2-yl)methylene!-2-indolinone;

3- (3,5-Dimethylpyrrol-2-yl)methylene!-5-nitro-2-indolinone;

3- (3-(2-carboxyethyl)-4-methylpyrrol-5-yl)methylene!-2-indolinone;

5-Chloro-3- (3,5-dimethylpyrrol-2-yl)methylene!-2-indolinone; and

3- (2,4-Dimethylpyrrol-5-yl)methylene!-2-indolinone, or a pharmaceutically acceptable salt thereof.

4. The compound of claim 3, wherein said compound is 3- (2,4-Dimethylpyrrol-5-yl)methylene!-2-indolinone, or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound according to claim 3.

11. The pharmaceutical composition of claim 10, wherein said compound is 3- (2,4-Dimethylpyrrol-5-yl)methylene!-2-indolinone, or a pharmaceutically acceptable salt thereof.

12. The pharmaceutical composition of claim 10, wherein said composition is suitable for parenteral administration to a subject.

13. The pharmaceutical composition of claim 10, wherein said composition is suitable for subcutaneous administration to a subject.

14. The pharmaceutical composition of claim 10, wherein said composition is in a depot formulation.

15. A method for treating diseases related to tyrosine kinase signal transduction, the method comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound having the formula:

##STR13## and pharmaceutically acceptable salts thereof, wherein;

R₁ is H or alkyl;

R₂ is O or S;

R₃ is hydrogen,

R₄, R₅, R₆, and R₇ are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO₂ NRR'"'"', SO₃ R, SR, NO₂, NRR'"'"', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH₃)_n CO₂ R, and CONRR'"'"';

A is a five membered heteroaryl ring selected from the group consisting of thiophene, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole, isothiazole, 2-sulfonylfuran, 4-alkylfuran, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3,4-thiatriazole, 1,2,3,5-thiatriazole, and tetrazole, optionally substituted at one or more positions with alkyl, alkoxy, aryl, aryloxy, alkaryl, akaryloxy, halogen, trihalomethyl, S(O)R, SO₂ NRR'"'"', SO₃ R, SR, NO₂, NRR'"'"', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH₂)_n CO₂ R, and CONRR'"'"';

n is 0-3;

R is H, alkyl or aryl; and

R'"'"' is H, alkyl or aryl.

16. The method of claim 15 wherein said disease is selected from the group consisting of cancer, blood vessel proliferative disorders, fibrotic disorders, mesangial cell proliferative disorders and metabolic diseases.

17. The method of claim 16 wherein the blood vessel proliferative disorder is selected from the group consisting of arthritis and restenosis.

18. The method of claim 16 wherein the fibrotic disorder is selected from the group consisting of hepatic cirrhosis and atherosclerosis.

19. The method of claim 16 wherein the mesangial cell proliferative disorder is selected from the group consisting of glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, transplant rejection and glomerulopathies.

20. The method of claim 16 wherein the metabolic disorder is selected from the group consisting of psoriasis, diabetes melitus wound healing, inflammation and neurogenerative diseases.

21. A method for regulating, modulating or inhibiting tyrosine kinase signal transduction comprising administering to a subject a therapeutically effective amount of a compound having the formula:

##STR14## and pharmaceutically acceptable salts thereof, wherein;

R₁ is H or alkyl;

R₁ is O or S;

R₃ is hydrogen;

R₄, R₅, and R₇ are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO₂ NRR'"'"', SO₃ R, SR, NO₂, NRR'"'"', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH₂)_n CO₂ R, and CONRR'"'"';

A is a five membered heteroaryl ring selected from the group consisting of thiopene, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole isothiazole, 2-sulfonylfuran, 4-alkylfuran, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, 1,2 3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3,4-thiatriazole, 1,2,3,5-thiatriazoke, and tetrazole, optionally substituted at one or more positions with alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO₂ NRR'"'"', SO₃ R, SR, NO₂, NRR'"'"', OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH₂)_n CO₂ R, and CONRR'"'"';

n is 0-3;

R is H, alkyl or aryl; and

R'"'"' is H, alkyl or aryl.

22. A method for treating diseases related to tyrosine kinase signal transduction, the method comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of 3- (3-Methylpyrrol-2-yl)methylene!-2-indolinone;

3- (3,4-Dimethylpyrrol-2-yl)methylene!-2-indolinone;

3- (2-Methylthien-5-yl)methylene!-2-indolinone;

3- (3-Methylthien-2-yl)methylene!-2-indolinone;

3-{ 4-(2-methoxycarbonylethyl)-3-methylpyrrol-5-yl!methylene}-2-indolinone;

3- (4,5-Dimethyl-3-ethylpyrrol-2-yl)methylene!-2-indolinone;

3- (5-Methylimidazol-2-yl)methylene!-2-indolinone;

5-Chloro-3- (5-methylthien-2-yl)methylene!-2-indolinone;

3- (3,5-Dimethylpyrrol-2-yl)methylene!-5-nitro-2-indolinone;

3- (3-(2-carboxyethyl)-4-methylpyrrol-5-yl)methylene!-2-indolinone;

5-Chloro-3- (3,5-dimethylpyrrol-2-yl)methylene!-2-indolinone;

3- (Thien-2-yl)methylene!-2-indolinone;

3- (Pyrrol-2-yl)methylene!-2-indolinone and 3- (2,4-Dimethylpyrrol-5-yl)methylene!-2-indolinone, or a pharmaceutically acceptable salt thereof.

23. The method of claim 22, wherein said disease is selected from the group consisting of cancer, blood vessel proliferative disorders, fibrotic disorders, mesangial cell proliferative disorders and metabolic diseases.

24. The method of claim 23, wherein the blood vessel proliferative disorder is selected from the group consisting of arthritis and restenosis.

25. The method of claim 23, wherein the fibrotic disorder is selected from the group consisting of hepatic cirrhosis and atherosclerosis.

26. The method of claim 23, wherein the mesangial cell proliferative disorder is selected from the group consisting of glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, transplant rejection and glomerulopathies.

27. The method of claim 23, wherein the metabolic disorder is selected from the group consisting of psoriasis, diabetes mellitus, wound healing, inflammation and neurodegenerative diseases.

28. A method for regulating, modulating or inhibiting tyrosine kinase signal transduction comprising administering to a subject a tyrosine kinase signal transduction comprising administering to a subject a therapeutically effective amount of a compound selected from the group consisting of 3- (3-Methylpyrrol-2-yl)methylene!-2-indolinone;

3- (3,4-Dimethylpyrrol-2-yl)methylene!-2-indolinone;

3- (2-Methylthien-5-yl)methylene!-2-indolinone;

3- (3-Methylthien-2-yl)methylene!-2-indolinone;

3-{ 4-(2-methoxycarbonylethyl)-3-methylpyrrol-5-yl!methylene}-2-indolinone;

3- (4,5-Dimethyl-3-ethylpyrrol-2-yl)methylene!-2-indolinone;

3- (5-Methylimidazol-2-yl)methylene!-2-indolinone;

5-Chloro-3- (5-methylthien-2-yl)methylene!-2-indolinone;

3- (3,5-Dimethylpyrrol-2-yl)methylene!-5-nitro-2-indolinone;

3- (3-(2-carboxyethyl)-4-methylpyrrol-5-yl)methylene!-2-indolinone;

5-Chloro-3- (3,5-dimethylpyrrol-2-yl)methylene!-2-indolinone;

3- (Thien-2-yl)methylene!-2-indolinone;

3- (Pyrrol-2-yl)methylene!-2-indolinone and 3- (2,4-Dimethylpyrrol-5-yl)methylene!-2-indolinone, or a pharmaceutically acceptable salt thereof.